CA1108629A - Maleic acid halfamides - Google Patents
Maleic acid halfamidesInfo
- Publication number
- CA1108629A CA1108629A CA318,131A CA318131A CA1108629A CA 1108629 A CA1108629 A CA 1108629A CA 318131 A CA318131 A CA 318131A CA 1108629 A CA1108629 A CA 1108629A
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- hydroxy
- group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention provides hemiamides of unsatur-ated aliphatic dicarboxylic acids having the general formula
The present invention provides hemiamides of unsatur-ated aliphatic dicarboxylic acids having the general formula
Description
11~8~Z9 The present invention relates to hemiamides having pharmacological properties and their preparation.
In Example 6 of the British Patent 1,137,596 the N-[2-(3-hydroxy-phenyl)-2-hydroxy-ethyl]-maleic monoamide having the formula HO \
--CH (OH ) -CH2-NH-CO-CH=CH-C02H
:
is disclosed. In the British Patent 1,137,596 an effect on the blood circulation, particularly a favourable effect in the case of low blood pressure, is mentioned as the pharmacological effect of these compounds.
Furthermore it is mentioned in the British Patent -~
901,438 that maleic-monoamide derivatives having the general formula --~ R-NH-CO-CH=CH-C02H
.
wherein Y represents hydrogen, a halogen atom, a Cl-C10-alkyl group or a Cl-C10-alkoxy group and R represents an ethylene or propylene group, which can also be substituted by Cl-C10 radicals and/or a hydroxy group, counteract the excretion of penicillin in the organism. Some of the compounds are said to be effective against gout and possibly reduce the cholesterol content in the blood.
According to the present invention there are provided hemiamides of unsaturated aliphatic dicarboxylic acids having the general formula ; 30 ~ ~ ( ) 4 (2)n 1 6 7 2 R2 ~ H
3 s `''~
i~8629 wherein Rl, R2 and R3 are identical or different and represent hydrogen, a halogen atom, a hydroxy ~roup, a methyl group or a methoxy qroup or two of these radicals together represent a ~ethylene-dioxy group, R4 is hydrogen or a methyl group, the radi-cals P~6 and R7 represent independently of each other, hydrogen or Cl-C4-alkyl groups, and n is 0 or 1, and their salts, the N-[2-(3-hydroxy-phenyl)-2-hydroxy-ethvl]-maleic monoamide being excluded in the case of the free acids.
~Ihen the radicals Rl, R2 or R3 are halogen atoms, then they represent fluorine, chlorine or bromine, particularly chlorine. ~Then the radicals R6 or R7 are alkyl groups, then they represent particularly methyl or ethyl groups.
The compounds according to the invention are pharma-codynamically effective and have, for example, an antidepressive effect. Furthermore the salts of the compounds according to the invention with phenvl-alkyl amines, particularly with nor-ephedrine, p-hydroxy-nor-ephedrine and other nor-ephedrine derivatives have remarkably long-lasting effects on the circulation (as for example, rise of blood pressure and positively inotropic effects) as well as an increased blood flow through the kidneys and a diuretic effectiveness.
The physiologically compatible salts with metals such as K, Na, Li, Mg, Ca or NH3 or with amines or organic compounds containina one or several basic nitrogen atoms are suitable as salts.
Examples of such amines or basic organic compounds are a) primary, secondary or tertiary aliphatic alkyl radicals having from 1 to 6 C atoms such as triethvl amine and diethyl amine C2-C6 alkylene diamines such as ethvlene diamine, and propylene diamine, primary, secondary or tertiary alkanol amines with alkylene radicals having from 2 to 6C atoms such as ethanol amine, diethanol amine and triethanol amine;
In Example 6 of the British Patent 1,137,596 the N-[2-(3-hydroxy-phenyl)-2-hydroxy-ethyl]-maleic monoamide having the formula HO \
--CH (OH ) -CH2-NH-CO-CH=CH-C02H
:
is disclosed. In the British Patent 1,137,596 an effect on the blood circulation, particularly a favourable effect in the case of low blood pressure, is mentioned as the pharmacological effect of these compounds.
Furthermore it is mentioned in the British Patent -~
901,438 that maleic-monoamide derivatives having the general formula --~ R-NH-CO-CH=CH-C02H
.
wherein Y represents hydrogen, a halogen atom, a Cl-C10-alkyl group or a Cl-C10-alkoxy group and R represents an ethylene or propylene group, which can also be substituted by Cl-C10 radicals and/or a hydroxy group, counteract the excretion of penicillin in the organism. Some of the compounds are said to be effective against gout and possibly reduce the cholesterol content in the blood.
According to the present invention there are provided hemiamides of unsaturated aliphatic dicarboxylic acids having the general formula ; 30 ~ ~ ( ) 4 (2)n 1 6 7 2 R2 ~ H
3 s `''~
i~8629 wherein Rl, R2 and R3 are identical or different and represent hydrogen, a halogen atom, a hydroxy ~roup, a methyl group or a methoxy qroup or two of these radicals together represent a ~ethylene-dioxy group, R4 is hydrogen or a methyl group, the radi-cals P~6 and R7 represent independently of each other, hydrogen or Cl-C4-alkyl groups, and n is 0 or 1, and their salts, the N-[2-(3-hydroxy-phenyl)-2-hydroxy-ethvl]-maleic monoamide being excluded in the case of the free acids.
~Ihen the radicals Rl, R2 or R3 are halogen atoms, then they represent fluorine, chlorine or bromine, particularly chlorine. ~Then the radicals R6 or R7 are alkyl groups, then they represent particularly methyl or ethyl groups.
The compounds according to the invention are pharma-codynamically effective and have, for example, an antidepressive effect. Furthermore the salts of the compounds according to the invention with phenvl-alkyl amines, particularly with nor-ephedrine, p-hydroxy-nor-ephedrine and other nor-ephedrine derivatives have remarkably long-lasting effects on the circulation (as for example, rise of blood pressure and positively inotropic effects) as well as an increased blood flow through the kidneys and a diuretic effectiveness.
The physiologically compatible salts with metals such as K, Na, Li, Mg, Ca or NH3 or with amines or organic compounds containina one or several basic nitrogen atoms are suitable as salts.
Examples of such amines or basic organic compounds are a) primary, secondary or tertiary aliphatic alkyl radicals having from 1 to 6 C atoms such as triethvl amine and diethyl amine C2-C6 alkylene diamines such as ethvlene diamine, and propylene diamine, primary, secondary or tertiary alkanol amines with alkylene radicals having from 2 to 6C atoms such as ethanol amine, diethanol amine and triethanol amine;
- 2 -- : -:-:: .
~86~9 b) ~-phenyl-Cl-C4 alkyl amines and ~-phenyl-Cl-C4-alkanol amines, wherein the phenyl radical can be substituted, for example by Cl-C5-alkyl groups, Cl-C5-alkoxy groups, hydroxyl groups, hydroxy-methyl groups or halogen atoms such as F, Cl, sr and wherein the amino group can also be substituted by Cl-C6-alkyl radicals, phenyl-Cl-C4-alkyl radicals which can also contain Cl-C5-alkyl groups, Cl-C5-alkoxy groups or hydroxyl groups in the phenyl nucleus or by Cl-C5-alkyl or C2-C5-alkenyl radicals, which are substituted by a heterocyclic radical for example, thienyl or pyridyl radicals and can also contain an oxo group or a hydroxy yroup in the alkyl or alkenyl component. Examples are nor-ephedrine, amphetamine, o-, p- or m-hydroxy-nor-ephedrine, 3,4-dihydroxy or 3,5-dihydroxy-nor-ephedrine, ~-(2-hydroxy-1-methyl-phenethyl amino)-3-methoxy propiophenone.
c) Diphenyl-C2-C6-alkyl amines whose amino group is substituted by straight or branched Cl-C5 alkyl radicals or phenyl-Cl-C4-alkyl groups for example, phenethyl group, phenyl-isopropyl group. Examples are N-(l-methyl-phenethyl)-3,3-diphenyl-propyl amine.
d) 1-aryl-oxy-propanol-2-amines whose amino group can be sub-stituted by Cl-C6-alkyl groups, phenyl-Cl-C4-alkyl groups for example, phenethyl group, phenyl-isopropyl group or hetero-cyclically e.g. by a pyridyl, thienyl or theophyllinyl or theo-bromin~l radical substituted C2-C6-alkenyl groups and whose aryl radical which can also be substituted represents a phenyl, naphthyl or tetrahydronaphthyl radical or a mono-, di- or tri-cyclic heteroaromatic ring system (examples are listed under f).
The aryl radical is particularly an ~-naphthyl radical, a phenyl radical, an o-allyl-oxy-phenyl radical, a p-allyl-oxy-phenyl radical, an indolyl-(4)-radical, a 2-methyl-indolyl-(4)-radical or a 2,3-dimethyl-indolyl radical.
e) Alkaloids containing one or several nitrogen atoms, as for example, atropine, hyoscyamine, scopolamine, codeine, ajmaline, and sparteine.
f) Basically substituted xanthine derivatives, particularly theophylline and theobromine derivatives having the general formula T - Alk - NH - CH - CH - R3 Rl R2 wherein T represents a dialkyl-xanthinyl radical, Alk represents a straight or branched C2-C6-alkylene group, Rl represents hydrogen or a Cl-C4-alkyl group, R2 represents hydrogen or a hydroxy group and R3 represents a phenyl radical, which, if required is substituted by hydroxy groups (particularly singly or doubly), Cl-C5-alkyl groups, Cl-C5 alkoxy groups, hydroxy-methyl groups or by the methylene-dioxy group, or an aryl-oxy-methyl radical, the naphthyl radical, the tetrahydronaphthyl radical or a mono-, di- or tricyclic heteroaromatic ring system being suitable as the aryl radical, said ring system can also be singly to trebly substituted by lower alkyl, alkoxy, alkenyl or alkenyl-oxy groups or by halogen atoms. Examples of the heteroaromatic ring system are indole, isoindole, benzimidazole, quinoline, dihydro quinoline, tetrahydroquinoline, isoquinoline, pyrazole, thiazole, methyl indole, methyl isoindole, methyl benzimi.dazole, methyl quinoline, methyl-dihydro quinoline, methyl tetrahydroquinoline, methyl isoquinoline, methyl pyrazole, methyl thiazole, dimethyl indole, dimethyl quinoline, dimethyl isoquinoline, dimethyl benzimidazole tin the bicyclic radicals ::
the methyl group or groups are preferably in the ring which con-tains the hetero atom).
30 . Salts in which the basic component has the formula II
A and the symbols Rl to R~ and n have the aforèsaid meanings.~have particularly favourable.effects. Examples are . . :
36;Z9 nor-ephedrin, p-hydroxy-nor-ephedrin, m-hydroxy-nor-ephedrine,
~86~9 b) ~-phenyl-Cl-C4 alkyl amines and ~-phenyl-Cl-C4-alkanol amines, wherein the phenyl radical can be substituted, for example by Cl-C5-alkyl groups, Cl-C5-alkoxy groups, hydroxyl groups, hydroxy-methyl groups or halogen atoms such as F, Cl, sr and wherein the amino group can also be substituted by Cl-C6-alkyl radicals, phenyl-Cl-C4-alkyl radicals which can also contain Cl-C5-alkyl groups, Cl-C5-alkoxy groups or hydroxyl groups in the phenyl nucleus or by Cl-C5-alkyl or C2-C5-alkenyl radicals, which are substituted by a heterocyclic radical for example, thienyl or pyridyl radicals and can also contain an oxo group or a hydroxy yroup in the alkyl or alkenyl component. Examples are nor-ephedrine, amphetamine, o-, p- or m-hydroxy-nor-ephedrine, 3,4-dihydroxy or 3,5-dihydroxy-nor-ephedrine, ~-(2-hydroxy-1-methyl-phenethyl amino)-3-methoxy propiophenone.
c) Diphenyl-C2-C6-alkyl amines whose amino group is substituted by straight or branched Cl-C5 alkyl radicals or phenyl-Cl-C4-alkyl groups for example, phenethyl group, phenyl-isopropyl group. Examples are N-(l-methyl-phenethyl)-3,3-diphenyl-propyl amine.
d) 1-aryl-oxy-propanol-2-amines whose amino group can be sub-stituted by Cl-C6-alkyl groups, phenyl-Cl-C4-alkyl groups for example, phenethyl group, phenyl-isopropyl group or hetero-cyclically e.g. by a pyridyl, thienyl or theophyllinyl or theo-bromin~l radical substituted C2-C6-alkenyl groups and whose aryl radical which can also be substituted represents a phenyl, naphthyl or tetrahydronaphthyl radical or a mono-, di- or tri-cyclic heteroaromatic ring system (examples are listed under f).
The aryl radical is particularly an ~-naphthyl radical, a phenyl radical, an o-allyl-oxy-phenyl radical, a p-allyl-oxy-phenyl radical, an indolyl-(4)-radical, a 2-methyl-indolyl-(4)-radical or a 2,3-dimethyl-indolyl radical.
e) Alkaloids containing one or several nitrogen atoms, as for example, atropine, hyoscyamine, scopolamine, codeine, ajmaline, and sparteine.
f) Basically substituted xanthine derivatives, particularly theophylline and theobromine derivatives having the general formula T - Alk - NH - CH - CH - R3 Rl R2 wherein T represents a dialkyl-xanthinyl radical, Alk represents a straight or branched C2-C6-alkylene group, Rl represents hydrogen or a Cl-C4-alkyl group, R2 represents hydrogen or a hydroxy group and R3 represents a phenyl radical, which, if required is substituted by hydroxy groups (particularly singly or doubly), Cl-C5-alkyl groups, Cl-C5 alkoxy groups, hydroxy-methyl groups or by the methylene-dioxy group, or an aryl-oxy-methyl radical, the naphthyl radical, the tetrahydronaphthyl radical or a mono-, di- or tricyclic heteroaromatic ring system being suitable as the aryl radical, said ring system can also be singly to trebly substituted by lower alkyl, alkoxy, alkenyl or alkenyl-oxy groups or by halogen atoms. Examples of the heteroaromatic ring system are indole, isoindole, benzimidazole, quinoline, dihydro quinoline, tetrahydroquinoline, isoquinoline, pyrazole, thiazole, methyl indole, methyl isoindole, methyl benzimi.dazole, methyl quinoline, methyl-dihydro quinoline, methyl tetrahydroquinoline, methyl isoquinoline, methyl pyrazole, methyl thiazole, dimethyl indole, dimethyl quinoline, dimethyl isoquinoline, dimethyl benzimidazole tin the bicyclic radicals ::
the methyl group or groups are preferably in the ring which con-tains the hetero atom).
30 . Salts in which the basic component has the formula II
A and the symbols Rl to R~ and n have the aforèsaid meanings.~have particularly favourable.effects. Examples are . . :
36;Z9 nor-ephedrin, p-hydroxy-nor-ephedrin, m-hydroxy-nor-ephedrine,
3,4-dihydroxy-nor-ephedrine, nor-adrenalin, ephedrine, 3,4-dihydroxy ephedrine.
The compounds according to the invention are produced by reacting a compound havi.ng the formula II
Rl :
~ -cH(oH)-cHR4-(cH2)n N 2 (II) R
with a compound having the formula III
X- CO - CR6 = CR7 - CO2H (III) in which compounds the radicals Rl-R4, R6 and R7 have the meanings defined hereinbefore with or without solvents at temperatures between 0 and 200C, particularlybetween 15and 150C. Suitablesol-vents and dispersing agents are: aromatic hydrocarbons such as benzene, toluene, xylene, aliphatic hydrocarbon halides such as chloroform, methylene chloride, non-cyclic or cyclic ethers such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, .alcohols such as ethanol, isopropanol, butanol, pyridine, tetra-methyl urea, dimethyl formamide, dimethyl sulphoxide, N-rnethyl pyrrolidone.
Sometimes it is advantageous to use the reaction compon-ent III in excess (particularly if X is an alkoxy group). If required, the addition of condensing agents such as dicyclohexyl carbo diimide, tetraethyl pyrophosphite, 5-(3'-sulphone-phenyl)-ethyl isoxazole, sulphurous acid-bis-alkyl amides (for example, SO[N(CH3)2]2) or N,N'-carbonyl-diimidazole (if X = OH) or the addition of basic substances (tertiary amines, alkali carbonates, alkali hydrogen carbonates, alkali acetates, alkaline earth carbonates, alkali hydroxides, etc.) is favourable. The amine component can also be added in the form of an acid addition .. - 5 -.. . ..
1~$~6Z9 salt; in this case the addition of acid-binding basic substances is usually required. If X of the compound III is a halogen atom 1:
then it is Cl, Br or I, preferably Cl or Br. If X of the com-pound III isan aryl-oxy group, then it is, for example, a .
phenoxy group, wherein the phenyl radical can also be substituted by lower alkyl radicals, lower alkoxy radicals, halogen atoms (Cl F, sr), nitro groups or cyano groups.
Hydroxy groups present in the starting compounds II, --: ~ ' ~':
- 5a -particularly phenolic hydroxy groups (if Rl, R2 and/or R3 = Ol~) and the carboxy group of the compound III can contain known and usual protective groups. They are radicals which can be readily split off by hydrolysis and, if required, are split off even during the reaction. If these protective groups are not split off during the reaction, then they are split off there-after. Because of their production the starting compounds frequently already contain these protective groups.
These protective groups are, for example, acyl groups which can be easily split off solvolytically. Said protective groups are split off, for example, by saponification with dilute acids or by means of basic substances (potash, soda, aqueous alkali solutions, alcoholic alkali solutions, NH3) at tempera-tures between 10 and 150C, particularly between 20 and 100C. --Examples of radicals which can be split off hydrolyti-cally are trifluoro-acetyl radical, phthalyl radical, trityl radical, p-toluene-sulphonyl radical and similar lower alkanoyl radicals such as acetyl radical, formyl radical, tertiary butyl-carboxy radical and the like.
. 20 The salts are produced by bringing the acids having the formula I into contact with the corresponding amines in a con-ventional solvent (lower aliphatic alcohols, lower aliphatic ketones, esters of lower aiiphatic acids with lower alcohols) at temperatures between 15 and 100C, particularly between 20 and 60C.
The components are usually used in equivalent amounts.
For example, in the case of the metallic salts the corresponding metallic hydroxide or metallic carbonate is used as the basic component.
For the racemic cleavage equivalent or non-equivalent amounts of the optically active hemiamide (0.4 to 1.2 moles), preferably 0.5 to 1.0 mole hemiamide per mole of base) and base .,, .: : .
: . ~ . : :.
can be reacted with each other in a solvent at temperatures between 0 and 100C, for example, between 10 and 40C, prefer-ably between 15 and 30C. The reaction can be carried out with or without stirring. If required, slow cooling during the crystallization is suitable. Seeding with the desired diastereo-isomeric salt previously produced from pure components can be recommended. As in other racemate cleavage processes the sol-yents or solvent mixtures to be applied are variable within a wide range. For example, alcohols such as methanol, ethanol, isopropanol, butanol, ketones such as acetone, methyl-ethyl ketone, methyl-isobutyl ketone, esters such as acetic ethyl ester and acetic butyl ester, amides such as dimethyl forr,lamide and dimethyl acetamide, ethers such as diethyl ether and dioxane, water, particularly in mixtures with organic solvents, are suit-able as solvents.
The amount of solvent, relative to the sum of the amounts of acid and base applied usually is twice to twenty times, the preferred range being from three to eight times.
For the reaction with the hemiamides the amines can be applied as correspondiny acids, preferably weak acids ~for example, acetate), if required. In such a case the hemiamide (amide acid) is applied as metallic salt (for example, alkali salt) if required.
In the reaction of the hemiamide I with the base one pure diastereomeric form precipitates directly while the other form remains in solution. However, if in one case or the other the precipitating diastereomeric form is rendered more intensely impure by the other form, the purification of this one form is carried out by fractional crystallization in the manner usually applied.
1~8629 The diastereomers obtained can be decomposed in a -simple manner, using alkali (for example, alkali metal hydrox-ides such as sodium or potassium hydroxide) ammonia or a mineral acid such as hydrochloric or sulphuric acid. The difficultly soluble diastereomer is treated, for example, with the alkali (preferably NH3 or ~aOH) and, in case that the base does not precipitate it is extracted with a solvent which is not compatible or not miscible with water such as chloroform, methylene chloride, benzene or ether. The opti-cally active base can then be isolated from the organic phase with a high degree of purity. The mother liquor, from which thedifficultly soluble diastereomer has been separated, is usually distilled off and the residue is absorbed in a solvent in which the residual (+~-base precipitates insolubly (for example, aromatic hydrocarbons such as toluene, xylene, benzene).
After several hours the (+)-base is separated and the filtrate is concentrated by evaporation while the other antipode of the base remains.
The aqueous phase, from which the optically active base has been extracted, is then acidified with a mineral acid (HCl, H2SO4) and the amide acid precipitates. The amide acids thus recovered can be reused directly for the racemate cleavage in most cases without further purification.
When the salts obtained in the racemate cleavage are decomposed with acids (mineral acids such as HCl, H2SO4) the amide acid precipitates first. The filtrate is rendered alka-..
. .
: - . , . , . ,:, ,: :. ..
il6!~8G;;~9 line either directly or after concentrating it and the optically active base is extracted with a solvent (lower aliphatic hydro-carbon halides such as chloroform or lower aliphatic dialkyl ether such as diethyl ether).
The racemate cleavage of (+)-p-hydroxy-nor-ephedrine is described hereafter by means of an example:
A mixture of 100 g of (+)-p-hydroxy-nor-ephedrine, 149 g of (-)-NEMA (see Example 2) and 1.25 litres of absolute ethyl alcohol is stirred for eight hours and allowed to stand for further 16 hours. The crystallized (-)-NE~A salt of the (-)-p-hydroxy-nor-ephedrine is filtered with suction and boiled with 550 ml of isopropanol for purification. On cooling the salt it is filtered with suction and dried at 60C in vacuo.
Yield: 94.3 g = 75.7~ of the theoretical yield; m.p. = 163 to 165C.
[~]20 (1% in absolute ethanol): +4.1.
Recovery of (-)-p-hydroxy-nor-ephedrine 94 g of this salt are stirred with 96 ml of 2N NaOH
for approximately one hour at room temperature and then allowed to stand over night in a refrigerator, followed by filtering with suction, washing with a small quantity of water and drying in vacuo at 40C.
Yield: 72.0%, m.p. = 162 to 166C
[~]D0 (2~ in absolute ethanol): -17.5 [~]D (3-5% in lN HCl): -40.7 Recovery of (+)-p-hydroxy-nor-ephedrine The ethanolic filtrate from the racemate cleavage is concentrated by evaporation in vacuo and the residue is recrys-tallized from isopropanol. 127.5 g of crude (-)-NEMA salt of (+)-p-hydroxy-nor-ephedrine are obtained. The (+)-base precipi-tates therefrom by stirring with 152 ml of 2N NaOH and allowing it to stand in a refrigerator for 12 hours, followed by filter-iZ9 ing with suction and recrystallizing from isopropanol.
- Yield = 60.4%; m.p. = 163 to 166C
[~]D (2% in absolute ethanol): +17.35 The salts of the final substances can be reconverted into the compounds I in a manner known per se, for example, with strong acids (for example, inorganic mineral acids) or ion exchangers.
sy compounds having the general formula I are also ~ -meant within the scope of the present invention the feasible stereoisomeric and optically active compounds and mixture thereof, particularly the racemates. Mixtures of diastereo-isomers can be separated in a known manner, for example, by fractional crystallization. Optically active substances can be obtained by means of the usual methods, for example, by recrystallizing salts of the racemic acids having the formula I
;th optically active bases or if required by using optically active starting products in the synthesis. The organic basic compounds suitable for the salt formation can also be present as purely optically active forms, as racemates or as dias-tereomers.
The compounds according to the invention are suitablefor the production of pharmaceutical compounds. The pharmaceu-tical compounds or medicaments can contain one or several of the compounds according to the invention or even mixtures there-of with other pharmaceutically active substances. Conventional pharmaceutical fillers and auxiliaries can be used for produc-ing the pharmaceutical preparations. The medicaments can be used enterally, parenterally, orally or perlingually. For example, they can be dispensed in the form of tablets, capsules, pills, dragees, suppositories or liquids. For example, oily or aqueous solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions are suitable as liquids.
~ , :
1~86~9 The compounds according to the invention are suitable for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or drugs contain, as the active substance, one or several compounds according to the invention, if required in mixture with other pharmacolog;cally or pharma-ceutically active substances. The drugs can be produced in a known -manner using the known and conventional pharmaceutical auxiliaries and other conventional fillers and diluents.-For example, substances which are recommended and/or listed in the following references from the literature as auxil-iaries for pharmacy, cosmetics and related fields are suitable as this kind of fillers and auxiliaries: Ullmann's ~ncyklopadie der technischen Chemie, Vol. ~ (1953), page 1 to 39; Journal of Pharmaceutical Sciences, Vol. 53 (1963), page 918 ff, H.v.Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie and angrenzende Gebiete; Pharm. Ind., No. 2, 1961, page 72 ff; Dr. H.P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Cantor KG., Aulendorf i. Wurtt. 1971.
Examples are gelatin, natural sugar such as sucrose or lactose, lecithin, pectin, starch (for example, cornstarch), alginic acid, tylose, talc, lycopodium, silica tfor example, colloidal silica), cellulose, cellulose derivatives (for example, cellulose ethers in which the cellulose-hydroxy groups are par-tially etherified with lower saturated aliphatic alcoholsand/or lower saturated aliphatic oxy-alcohols, for example, methyl-oxypropyl cellulose), stearates, magnesium and calcium salts of fatty acids, containing 12 to 22 C atoms, particularly of the saturated ones (for examples, stearates), emulsifiers, oils and fats, particularly vegetable oils ~for example, peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower oil, cod liver oil, mono-, di- and triglycerides of ' 1~8~9 saturated fatty acids Cl2H24O2 to C18H36O2 and their mixtures), pharmaceutically compatlble monohydric or polyhydric alcohols and polygIycols such as polyethylene glycols as well as deri-vatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 C atoms, particularly 10 to 18 C atoms) with monohydric aliphatic alochols (1 to 20 C atoms) or poly-hydric alcohols such as glycols, glycerin, diethylene glycol, pentaerythrite, sorbite, mannite, etc., which, if required, .
can also be etherified, benzyl benzoate, dioxolanes, glycerin formals, tetrahydrofurfuryl alcohol, polyglycol ethers with Cl -C12 alcohols, dimethyl acetamide, lactamides, lactates, ethyl carbonates, silicones (particularly medium-viscosity dimethyl polysiloxanes) magnesium carbonate and the like.
For example, water or physiologically compatible organic solvents are suitable for the production of solutions, as for example, ethanol, 1,2-propylene glycol, polyglycols and their derivatives, dimethyl sulphoxide, fat alcohols, trigly-cerides, partial esters of glycerin, paraffins and the like.
For the production of the preparations known and conventional dissolving intermediaries and emulsifiers can be used, as for example, polyvinyl pyrrolidone, sorbitan fatty esters such as sorbitan trioleate, lecithin, acacia gum, gum tragacanth, polyoxy-ethylated sorbitan monooleate, polyoxy-ethylated fats, polyoxy-ethylated oleotriglycerides, linolized oleotriglyceridesjpolyethylene-oxide condensation products of fat alcohols, alkyl phenols or fatty acids. In this connection "polyoxy-ethylated" means that the substances concerned contain polyoxy-ethylene chains whose degree of polymerization usually is between 2 and 40 and particularly between lO and 20.
i29 These polyoxy-ethylated substances can be obtained, for example, by reactions of compounds containing hydroxyl groups (as for example, mono- or diglycerides or unsaturated compounds, as for example, those containing oleic acid radicals) with ethylene oxide (for example, 40 moles of ethylene oxide per mole of glyceride).
Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil (see Dr. H.P. Fiedler "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete" 1971, page 191 to 195).
Moreover, the addition of preservatives, stabilizers, buffer substances, for example, calcium hydrogen phosphate, colloidal aluminium hydroxide, taste corrigents, antioxidants and complexing agents (for example, ethylene diamino tetraacetic acid) and the like is possible. If required, the pH range may be ad~usted for the stabilization of the active substance molecule to approximately 3 to 7 with physiologically compatible acids or buffers. In general, a pH value asneutral as possible to weakly acid (to pH 5) is preferred.
For example, sodium metabisulphite, ascorbic acid,~
gallic acid, gallic alkyl ester, butyl hydroxy anisole, nor- ~
dihydro guaiaric acid, tocopherols as well as tocopherols +
synergists (substances which bind heavy metals by complexing action, for example, lecithin. ascorbic acid, phosphoric acid) are used as antioxidants. The addition of the synergists sub-stantially increases the antioxygenating action of the tocopherols.
For example, sorbic acid, p-hydroxy benzoic esters (for example, lower alkyl ester), benzoic acid, sodium benzoate, trich~oro isobutyl alcohol, phenol, cresol, benzethonium chloride and ~ormalin derivatives are suitable as preservatives.
i29 The pharmacological and galenic handling of the compounds according to the invention is carried out by means of the conventional standard methods. For example, active substance(s) and auxiliaries and/or fillers are properly mixed by stirring or homogenizing (for example, by means of colloid mills, ball mills) usually at temperatures between 20 and 80C, preferably between 20 and 50C.
The active substances or drugs can be applied to the skin or mucous membrane or parenterally for example, orally, enterally, pulmonarily, rectally, nasally, vaginally, lingually, -~
- intravenously, intraarterially, intracardially, intramuscularly, ~
intraperitoneally, intracutaneously, subcutaneously. ;
The addition of other active medical substances is possible.
The compounds according to the invention show a circu-lation-stimulating, particularly a blood-pressure-increasing effect on anaesthetized animals when measuring blood pressure, contractility and heart time volume.
The measurement of the blood pressure was carried out in the usual manner with electronic pressure followers (Statham) directly (sanguineously). The contractility (dp/dtmaX) was deter-mined from the pressure of the left heart ventricle (method accord-ing to Schaper et al. Arch. Kreislaufforsch. 46, 27, 1965). The heart time volume was determined by means of the cold dilution method (according to Hamilton, W.F. et al, Am. J. Physiol. 99, 543, 1932) with the aid of a fixed-program analog computer (method according to Slama, H. and Piiper, J. Kreislaufforschung 53, 322 (1964)).
For example, in the above method of testing at a dose of 1 mg/body weight of dog the average arterial mean pressure is increased by approximately 20 % and the heart time volume by approximately 100 %. The contractility (rate of pressure rise) ; is increased by approximately 70%.
Çi29 ....
This circulation-stimulating action is comparable to the action of the known drug nor-ephedrine.
The lowest blood-pressure-rising effective dose in the above animal test is, for example, 0.3 mg/kg orally and 0.1 mg/kg intravenously.
For example, 1 to 10 mg/kg, particularly 3 mg/kg orally and o.l to 1 mg/kg, particularly 0.3 mg/kg intravenously are suitable as a general dose range for the blood-pressure-rising effect (animal test as above).
Indications for which the compounds according to the invention can be considered are: disorders due to shock, hypotonia, orthostatic disorders, collapse.
The pharmaceutical preparations usually contain between 1 and 50 mg of the active component(s) according to the invention.
Theycan be dispensed, for example, in the form of tablets, capsules, pills, dragées, suppositories, aerosols or in a liquid form. For example, oily or alcoholic or aqueous solutions as well as suspensions and emulsions are suitable as liquid forms of application. Tablets containing between 1 and 50 mg or`solutions containing from 1 to 5% of active substance are preferred forms of applications.
The single dose of the active components according to the invention can be, for example, a) in the form of drugs applied orally between 5 and 40 mg b) in the form of drugs applied parenterally (for example, intravenously, intramuscularly) between 1 and 20 mg c) for drugs to be inhaled (solutions or aerosols) between 1 and 5 mg d) in the form of drugs to be applied rectally or vaginally between 5 and 30 mg.
(In all the cases the doses are relative to the free base.) For example, three times daily 1 to 3 tablets containing 5 to 40 mg of active substance can be recommended or, for example, for intravenous injection 1 to 6 times daily 1 ampule of 1 to 10 ml containing from 1 to 20 mg of substance. For oral application the minimum daily dose is, for example, 10 whereas the maximum daily dose mustnot exceed 120.
For the treatment of dogs and cats the single oral dose usually is between approximately 1 and 20 mg per kg of body weight and the parenteral dose is approximately between 0.1 and 3 mg per kg of body weight.
For the treatment of horses and cattle the single oral ~ -dose usually is between approximately 1 and 20 mg/kg of body weight and the single parenteral dose is approximately 0.1 and 3 mg per kg of body weight. ;
In mice the acute toxicity of the compounds according to the invention (expressed by the LD 50 mg/kg; method according to Miller and Tainter: Proc. Soc. Exper. Biol. a. Med. 57 (1944) 261) is, for example, for oral application above 500 mg/kg.
The drugs can be used in human medicine, in veterinary medicine and in agriculture, either alone or in mixture with other pharmacologically active substances.
Examples of Pharmaceutical Preparations Example of Tablets 25 g of (-)-nor-ephedrine salt of ~ NEMA are mixed with 25 g of colloidal silica, 5 g of cornstarch and 60 g of lac-tose. The powder is granulated with a solution of 2.5 g of methyl-oxy-propyl cellulose in approximately 80 ml of a 30% ethanol. The dried granulate is mixed with 10.5 g of cornstarch, 9 g of talc, 62.5 g of micro-crystalline cellulose and 0.5 g of magnesium stearate and then moulded into tablets in a known manner.
One tabletweighing 200 mg contains 25 mg of active substance.
.. . . ..
Example of an Injection Solution 10 mg of (-)-hydroxy-nor-ephedrine salt of (-)-NEMA
are dissolved in 200 mg of propylene glycol and the solution is made up to 2.0 ml with bidistilled water. The solution is fil-tered through a sterile filter and then filled into ampules under aseptic conditions.
~86Z9 The free acids having the general formula I also are valuable racemic-cleavage reagents for racemic bases and there-fore are important particularly for the production of optically active pharmaceutical active substances.
Example 1 (+)-~-N-(l-methyl-2-phenyl-2-hydroxy-ethyl)-maleic monoamide (abbreviated: (+)-~-NEMA) 165.4 g of maleic anhydride are dissolved in 1250 ml of warm toluene. A warm (50C) solution of 255 g of t-)-~-nor-ephedrine in 1250 ml of toluene is rapidly added dropwise while stirring, whereupon stirrin~ is continued for one hour at an internal temperature of 80C. The- solution is then cooled to room temperature. The crystallized amide acid is filtered with suc-tion and dried in vacuo at 60C.~
Yield: 419.9 g = 99.9~ of the theoretical yield.
After the recrystallization the reaction product has a melting point of 152 to 155C.
[]20 (2.S% in a 96% ethanol): +17.64.
(-)-nor-ephedrine salt - 25 g of (-)-nor-ephedrine and 41.2 g of (+)-~-NE~ are dissolved in 200 ml of acetone while hot. The salt crystallizes upon cooling.
Yield: 64.5 g = 97.6% of the theoretical yield; m.p. = 149 to 151C.
[]D (2.5% in ethanol): -64.4 Example 2 -N-~l-methyl-2-phenyl-2-hydroxy-ethyl)-maleic monoamide (abbreviated: (-)-NEMA
16.3 g of maleic anhydride are dissolved in 300 ml of toluene. A warm (50C) solution of 25.0 g of (-)-nor-ephedrine in 50 ml of toluene is added dropwise to this solution while stirring, At this temperature stirring is continued for one ;
hour, followed by cooling and filtering with suction. The pro-duct is recrystallized from acetic ethyl ester in order to purify it.
Yield: 32.6 g = 79% of the theoretical yield; m.p. = 155 to 158C.
[a]20 (5% in ethanol): -7.69 (-)-ephedrine salt 20.6 g of (-)-ephedrine and 31 g of (-)-NEMA are dis-solved in 155 ml of acetone. The solution is mixed with dry ether until the turbidity is permanent. The mixture is allowed to stand for several days at room temperature whereupon it is filtered with suction and dried in vacuo.
Yield: 37.5 g = 73% of the theoretical yield; m.p. = 118 to [a]D (1% in a 96% ethanol): -39.5 (-)-nor-ephedrine salt 25 g of t-)-nor-ephedrine and 41.2 g of (-)-NEMA are dissolved in 200 ml of acetone while hot. The solution is then cooled and the crystalline salt is iltered with suction.
Yield: 56.3 g = 85% of the theoretical yield; m.p. = 142 to 144C
la]D (1% in ethanol): +7.39.
-nor-ephedrine salt 34.5 g of (-)-~ - nor-ephedrine and 57 g of (-)-NEMA
are dissolved in 460 ml of acetic ester while hot. The solu-tion-is cooled to room temperature, filtered with suction and dried.
Yield: 90.5 g = 98.4~ of the theoretical yield; m.p. = 153 to 155C.
Ia~D (1% in ethanol): 7.70~
(-)-p-hydroxy-nor-ephedrine salt 10 g of (-)-p-hydroxy-nor-ephedrine and 14.9 g of (-)-NEMA are stirred in 125 ml of isopropanol for two hours and , then allowed to stand for 15 hours at 20C, followed by filter-ing with suction and drying at 50C in vacuo.
Yield: 23.5 g = 94.4% of the theoretical yield; m.p. = 162 to 164C. -~
[]20 (1% in ethanol): +3.8 This salt can also be obtained from racemic p-hydroxy-nor-ephedrine by utilizing the~racemate-splitting properties of the maleic amide according to example 2: - a mixture of 100 g of (+)-p-hydroxy-nor-ephedrine, 149 g of (-)-NEMA and 1.25 litres of absolute ethyl alcohol is stirred for eight hours at 20C ;
and then allowed to stand for further 16 hours. The crystallized (-)-NEMA salt of the (-)-p-hydroxy-nor-ephedrine is filtered with suction and boiled with 550 ml of isopropanol in order to purify it, whereupon it is cooled, filtered with suction and dried in vacuo at 60C.
Yield: 94.3 g = 75.7% of the theoretical yield; m.p. = 163 to [a]20 (1% in absolute ethanol): +4.1 Example 3 (-)-~-N-(l-methyl-2-phenyl-2-hydroxy-ethyl)-methyl-maleic mono-amide A mixture of 14 g of citraconic anhydride and 18.9 g of (-)-~-nor-ephedrine is stirred in 180 ml of dimethyl forma- - !
mide for five hours at 40 to 50C. The mixture is then cooled and mixed with additional 18.9 g of (-)-~-nor-ephedrine while stirring. The reaction solution obtained is filtered and the solvent is distilled off in vacuo. The remaining salt is dis-solved in cold water and after acidifyingwith hydrochloric acid it is stirred for one hour, followed by filtering with suction, washing with water and drying in vacuo at 60C.
m.p. = 137 to 140C
[a]20 (2.5% in a 96% ethanol): -1.6 ~Yi, .
1~36Z9 , Example 4 (+)-N-~l-methyl-2-phenyl-2-hydroxy-ethyl)-maleic monoamide (abbreviated: (+)-NEMA) 32.6 g of maleic anhydride are dissolved in 600 ml of toluene and, while stirring, a warm (50C) solution of 50.0 g of (+)-nor-ephedrine in 100 ml of toluene is added dropwise.
At this temperature stirring is continued for 30 minutes, followed by cooling, filtering with sucti-on, drying and crystal-lizing from acetic ethyl ester.
Yield: 63.5 g = 77.0% of the theoretical yield; m.p. = 154 to [a]D (5% in ethanol)~ + 7.8 (+)-nor-ephedrine salt 50 g of (+)-nor-ephedrine and 82.4 g of (+)-~EMA are dissolved in 400 ml of isopropanol while warm. The solution is filtered and cooled -slowly to 5C. The crystallized salt is filtered with suction and dried in'vacuo at 60C.
Yield: 118.3 g = 89.5 g of the theoretical yield; m.p. = 141 to 143C.
20 I~] DO ( 1% in ethanol): -7.40 (+)-~-nor-ephedrine salt 34.5 g of ~+)-~-nor-ephedrine and 57 g of (+)-NEMA
are dissolved in 460 ml of acetic ester while hot. After cool-ing to room temperature the solution is filtered with suction and dried.
Yield; 90.S g = 98.4% of the theoretical yield; m.p. = 153 to 156C.
1~]D (1% in ethanol): -7.70 Example 5 (-)-N-(l-metbyl-2-p-hydroxy-phenyl-2-hydroxy-ethyl~-maleic monoamide (abbreviated: (-)-p-hydroxy-NEMA) S0 g of (-)-p-hydroxy-nor-ephedrine along with 29.3 g _ 20 -.
. . ,.: .. :
2g of maleic anhydride are stirred in 100 ml of dimethyl formamide.
After a weakly exothermic reaction fades the mixture is heated to 80C and kept for 1 hour at this temperature and is then mixed with 100 ml of water and stirréd for one hour. It is filtered with suction the next day and dried in vacuo.
Yield: 76.1 g = 96% of the theoretical yield; m.p. = 146 to 148C.
It is subsequently purified with cold isopropanol, filtered with suction and dried.
m.p. = 150 to 152C
[~]D (2% in a 96% ethanol): -13.05 Example 6 (+)-N-(l-methyl-2-p-hydroxy-phenyl-2-hydroxy-ethyl)-maleic monoamide (abbreviated: (+)-p-hydroxy-NEMA) 100 g of (+)-p-hydroxy-nor-ephedrine and 60.8 g of maleic anhydride are stirred in 150 ml dimethyl formamide.
After a weakly exothermic reaction fades the mixture is heated ~ -to ~0C and kept for one hour at this temperature and is then mixed with 100 ml of water and stirred for one hour. It is filtered with suction the next day and dried in vacuo.
yield~ 120 g of pure (+)-p-hydroxy-NE~A; m.p. = 151 to 153C
ta]20 (2% in a 96% ethanol): +12.9 Isopropanol can also be used as the solvent instead of dimethyl formamide~
_ 21 -
The compounds according to the invention are produced by reacting a compound havi.ng the formula II
Rl :
~ -cH(oH)-cHR4-(cH2)n N 2 (II) R
with a compound having the formula III
X- CO - CR6 = CR7 - CO2H (III) in which compounds the radicals Rl-R4, R6 and R7 have the meanings defined hereinbefore with or without solvents at temperatures between 0 and 200C, particularlybetween 15and 150C. Suitablesol-vents and dispersing agents are: aromatic hydrocarbons such as benzene, toluene, xylene, aliphatic hydrocarbon halides such as chloroform, methylene chloride, non-cyclic or cyclic ethers such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, .alcohols such as ethanol, isopropanol, butanol, pyridine, tetra-methyl urea, dimethyl formamide, dimethyl sulphoxide, N-rnethyl pyrrolidone.
Sometimes it is advantageous to use the reaction compon-ent III in excess (particularly if X is an alkoxy group). If required, the addition of condensing agents such as dicyclohexyl carbo diimide, tetraethyl pyrophosphite, 5-(3'-sulphone-phenyl)-ethyl isoxazole, sulphurous acid-bis-alkyl amides (for example, SO[N(CH3)2]2) or N,N'-carbonyl-diimidazole (if X = OH) or the addition of basic substances (tertiary amines, alkali carbonates, alkali hydrogen carbonates, alkali acetates, alkaline earth carbonates, alkali hydroxides, etc.) is favourable. The amine component can also be added in the form of an acid addition .. - 5 -.. . ..
1~$~6Z9 salt; in this case the addition of acid-binding basic substances is usually required. If X of the compound III is a halogen atom 1:
then it is Cl, Br or I, preferably Cl or Br. If X of the com-pound III isan aryl-oxy group, then it is, for example, a .
phenoxy group, wherein the phenyl radical can also be substituted by lower alkyl radicals, lower alkoxy radicals, halogen atoms (Cl F, sr), nitro groups or cyano groups.
Hydroxy groups present in the starting compounds II, --: ~ ' ~':
- 5a -particularly phenolic hydroxy groups (if Rl, R2 and/or R3 = Ol~) and the carboxy group of the compound III can contain known and usual protective groups. They are radicals which can be readily split off by hydrolysis and, if required, are split off even during the reaction. If these protective groups are not split off during the reaction, then they are split off there-after. Because of their production the starting compounds frequently already contain these protective groups.
These protective groups are, for example, acyl groups which can be easily split off solvolytically. Said protective groups are split off, for example, by saponification with dilute acids or by means of basic substances (potash, soda, aqueous alkali solutions, alcoholic alkali solutions, NH3) at tempera-tures between 10 and 150C, particularly between 20 and 100C. --Examples of radicals which can be split off hydrolyti-cally are trifluoro-acetyl radical, phthalyl radical, trityl radical, p-toluene-sulphonyl radical and similar lower alkanoyl radicals such as acetyl radical, formyl radical, tertiary butyl-carboxy radical and the like.
. 20 The salts are produced by bringing the acids having the formula I into contact with the corresponding amines in a con-ventional solvent (lower aliphatic alcohols, lower aliphatic ketones, esters of lower aiiphatic acids with lower alcohols) at temperatures between 15 and 100C, particularly between 20 and 60C.
The components are usually used in equivalent amounts.
For example, in the case of the metallic salts the corresponding metallic hydroxide or metallic carbonate is used as the basic component.
For the racemic cleavage equivalent or non-equivalent amounts of the optically active hemiamide (0.4 to 1.2 moles), preferably 0.5 to 1.0 mole hemiamide per mole of base) and base .,, .: : .
: . ~ . : :.
can be reacted with each other in a solvent at temperatures between 0 and 100C, for example, between 10 and 40C, prefer-ably between 15 and 30C. The reaction can be carried out with or without stirring. If required, slow cooling during the crystallization is suitable. Seeding with the desired diastereo-isomeric salt previously produced from pure components can be recommended. As in other racemate cleavage processes the sol-yents or solvent mixtures to be applied are variable within a wide range. For example, alcohols such as methanol, ethanol, isopropanol, butanol, ketones such as acetone, methyl-ethyl ketone, methyl-isobutyl ketone, esters such as acetic ethyl ester and acetic butyl ester, amides such as dimethyl forr,lamide and dimethyl acetamide, ethers such as diethyl ether and dioxane, water, particularly in mixtures with organic solvents, are suit-able as solvents.
The amount of solvent, relative to the sum of the amounts of acid and base applied usually is twice to twenty times, the preferred range being from three to eight times.
For the reaction with the hemiamides the amines can be applied as correspondiny acids, preferably weak acids ~for example, acetate), if required. In such a case the hemiamide (amide acid) is applied as metallic salt (for example, alkali salt) if required.
In the reaction of the hemiamide I with the base one pure diastereomeric form precipitates directly while the other form remains in solution. However, if in one case or the other the precipitating diastereomeric form is rendered more intensely impure by the other form, the purification of this one form is carried out by fractional crystallization in the manner usually applied.
1~8629 The diastereomers obtained can be decomposed in a -simple manner, using alkali (for example, alkali metal hydrox-ides such as sodium or potassium hydroxide) ammonia or a mineral acid such as hydrochloric or sulphuric acid. The difficultly soluble diastereomer is treated, for example, with the alkali (preferably NH3 or ~aOH) and, in case that the base does not precipitate it is extracted with a solvent which is not compatible or not miscible with water such as chloroform, methylene chloride, benzene or ether. The opti-cally active base can then be isolated from the organic phase with a high degree of purity. The mother liquor, from which thedifficultly soluble diastereomer has been separated, is usually distilled off and the residue is absorbed in a solvent in which the residual (+~-base precipitates insolubly (for example, aromatic hydrocarbons such as toluene, xylene, benzene).
After several hours the (+)-base is separated and the filtrate is concentrated by evaporation while the other antipode of the base remains.
The aqueous phase, from which the optically active base has been extracted, is then acidified with a mineral acid (HCl, H2SO4) and the amide acid precipitates. The amide acids thus recovered can be reused directly for the racemate cleavage in most cases without further purification.
When the salts obtained in the racemate cleavage are decomposed with acids (mineral acids such as HCl, H2SO4) the amide acid precipitates first. The filtrate is rendered alka-..
. .
: - . , . , . ,:, ,: :. ..
il6!~8G;;~9 line either directly or after concentrating it and the optically active base is extracted with a solvent (lower aliphatic hydro-carbon halides such as chloroform or lower aliphatic dialkyl ether such as diethyl ether).
The racemate cleavage of (+)-p-hydroxy-nor-ephedrine is described hereafter by means of an example:
A mixture of 100 g of (+)-p-hydroxy-nor-ephedrine, 149 g of (-)-NEMA (see Example 2) and 1.25 litres of absolute ethyl alcohol is stirred for eight hours and allowed to stand for further 16 hours. The crystallized (-)-NE~A salt of the (-)-p-hydroxy-nor-ephedrine is filtered with suction and boiled with 550 ml of isopropanol for purification. On cooling the salt it is filtered with suction and dried at 60C in vacuo.
Yield: 94.3 g = 75.7~ of the theoretical yield; m.p. = 163 to 165C.
[~]20 (1% in absolute ethanol): +4.1.
Recovery of (-)-p-hydroxy-nor-ephedrine 94 g of this salt are stirred with 96 ml of 2N NaOH
for approximately one hour at room temperature and then allowed to stand over night in a refrigerator, followed by filtering with suction, washing with a small quantity of water and drying in vacuo at 40C.
Yield: 72.0%, m.p. = 162 to 166C
[~]D0 (2~ in absolute ethanol): -17.5 [~]D (3-5% in lN HCl): -40.7 Recovery of (+)-p-hydroxy-nor-ephedrine The ethanolic filtrate from the racemate cleavage is concentrated by evaporation in vacuo and the residue is recrys-tallized from isopropanol. 127.5 g of crude (-)-NEMA salt of (+)-p-hydroxy-nor-ephedrine are obtained. The (+)-base precipi-tates therefrom by stirring with 152 ml of 2N NaOH and allowing it to stand in a refrigerator for 12 hours, followed by filter-iZ9 ing with suction and recrystallizing from isopropanol.
- Yield = 60.4%; m.p. = 163 to 166C
[~]D (2% in absolute ethanol): +17.35 The salts of the final substances can be reconverted into the compounds I in a manner known per se, for example, with strong acids (for example, inorganic mineral acids) or ion exchangers.
sy compounds having the general formula I are also ~ -meant within the scope of the present invention the feasible stereoisomeric and optically active compounds and mixture thereof, particularly the racemates. Mixtures of diastereo-isomers can be separated in a known manner, for example, by fractional crystallization. Optically active substances can be obtained by means of the usual methods, for example, by recrystallizing salts of the racemic acids having the formula I
;th optically active bases or if required by using optically active starting products in the synthesis. The organic basic compounds suitable for the salt formation can also be present as purely optically active forms, as racemates or as dias-tereomers.
The compounds according to the invention are suitablefor the production of pharmaceutical compounds. The pharmaceu-tical compounds or medicaments can contain one or several of the compounds according to the invention or even mixtures there-of with other pharmaceutically active substances. Conventional pharmaceutical fillers and auxiliaries can be used for produc-ing the pharmaceutical preparations. The medicaments can be used enterally, parenterally, orally or perlingually. For example, they can be dispensed in the form of tablets, capsules, pills, dragees, suppositories or liquids. For example, oily or aqueous solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions are suitable as liquids.
~ , :
1~86~9 The compounds according to the invention are suitable for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or drugs contain, as the active substance, one or several compounds according to the invention, if required in mixture with other pharmacolog;cally or pharma-ceutically active substances. The drugs can be produced in a known -manner using the known and conventional pharmaceutical auxiliaries and other conventional fillers and diluents.-For example, substances which are recommended and/or listed in the following references from the literature as auxil-iaries for pharmacy, cosmetics and related fields are suitable as this kind of fillers and auxiliaries: Ullmann's ~ncyklopadie der technischen Chemie, Vol. ~ (1953), page 1 to 39; Journal of Pharmaceutical Sciences, Vol. 53 (1963), page 918 ff, H.v.Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie and angrenzende Gebiete; Pharm. Ind., No. 2, 1961, page 72 ff; Dr. H.P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Cantor KG., Aulendorf i. Wurtt. 1971.
Examples are gelatin, natural sugar such as sucrose or lactose, lecithin, pectin, starch (for example, cornstarch), alginic acid, tylose, talc, lycopodium, silica tfor example, colloidal silica), cellulose, cellulose derivatives (for example, cellulose ethers in which the cellulose-hydroxy groups are par-tially etherified with lower saturated aliphatic alcoholsand/or lower saturated aliphatic oxy-alcohols, for example, methyl-oxypropyl cellulose), stearates, magnesium and calcium salts of fatty acids, containing 12 to 22 C atoms, particularly of the saturated ones (for examples, stearates), emulsifiers, oils and fats, particularly vegetable oils ~for example, peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower oil, cod liver oil, mono-, di- and triglycerides of ' 1~8~9 saturated fatty acids Cl2H24O2 to C18H36O2 and their mixtures), pharmaceutically compatlble monohydric or polyhydric alcohols and polygIycols such as polyethylene glycols as well as deri-vatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 C atoms, particularly 10 to 18 C atoms) with monohydric aliphatic alochols (1 to 20 C atoms) or poly-hydric alcohols such as glycols, glycerin, diethylene glycol, pentaerythrite, sorbite, mannite, etc., which, if required, .
can also be etherified, benzyl benzoate, dioxolanes, glycerin formals, tetrahydrofurfuryl alcohol, polyglycol ethers with Cl -C12 alcohols, dimethyl acetamide, lactamides, lactates, ethyl carbonates, silicones (particularly medium-viscosity dimethyl polysiloxanes) magnesium carbonate and the like.
For example, water or physiologically compatible organic solvents are suitable for the production of solutions, as for example, ethanol, 1,2-propylene glycol, polyglycols and their derivatives, dimethyl sulphoxide, fat alcohols, trigly-cerides, partial esters of glycerin, paraffins and the like.
For the production of the preparations known and conventional dissolving intermediaries and emulsifiers can be used, as for example, polyvinyl pyrrolidone, sorbitan fatty esters such as sorbitan trioleate, lecithin, acacia gum, gum tragacanth, polyoxy-ethylated sorbitan monooleate, polyoxy-ethylated fats, polyoxy-ethylated oleotriglycerides, linolized oleotriglyceridesjpolyethylene-oxide condensation products of fat alcohols, alkyl phenols or fatty acids. In this connection "polyoxy-ethylated" means that the substances concerned contain polyoxy-ethylene chains whose degree of polymerization usually is between 2 and 40 and particularly between lO and 20.
i29 These polyoxy-ethylated substances can be obtained, for example, by reactions of compounds containing hydroxyl groups (as for example, mono- or diglycerides or unsaturated compounds, as for example, those containing oleic acid radicals) with ethylene oxide (for example, 40 moles of ethylene oxide per mole of glyceride).
Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil (see Dr. H.P. Fiedler "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete" 1971, page 191 to 195).
Moreover, the addition of preservatives, stabilizers, buffer substances, for example, calcium hydrogen phosphate, colloidal aluminium hydroxide, taste corrigents, antioxidants and complexing agents (for example, ethylene diamino tetraacetic acid) and the like is possible. If required, the pH range may be ad~usted for the stabilization of the active substance molecule to approximately 3 to 7 with physiologically compatible acids or buffers. In general, a pH value asneutral as possible to weakly acid (to pH 5) is preferred.
For example, sodium metabisulphite, ascorbic acid,~
gallic acid, gallic alkyl ester, butyl hydroxy anisole, nor- ~
dihydro guaiaric acid, tocopherols as well as tocopherols +
synergists (substances which bind heavy metals by complexing action, for example, lecithin. ascorbic acid, phosphoric acid) are used as antioxidants. The addition of the synergists sub-stantially increases the antioxygenating action of the tocopherols.
For example, sorbic acid, p-hydroxy benzoic esters (for example, lower alkyl ester), benzoic acid, sodium benzoate, trich~oro isobutyl alcohol, phenol, cresol, benzethonium chloride and ~ormalin derivatives are suitable as preservatives.
i29 The pharmacological and galenic handling of the compounds according to the invention is carried out by means of the conventional standard methods. For example, active substance(s) and auxiliaries and/or fillers are properly mixed by stirring or homogenizing (for example, by means of colloid mills, ball mills) usually at temperatures between 20 and 80C, preferably between 20 and 50C.
The active substances or drugs can be applied to the skin or mucous membrane or parenterally for example, orally, enterally, pulmonarily, rectally, nasally, vaginally, lingually, -~
- intravenously, intraarterially, intracardially, intramuscularly, ~
intraperitoneally, intracutaneously, subcutaneously. ;
The addition of other active medical substances is possible.
The compounds according to the invention show a circu-lation-stimulating, particularly a blood-pressure-increasing effect on anaesthetized animals when measuring blood pressure, contractility and heart time volume.
The measurement of the blood pressure was carried out in the usual manner with electronic pressure followers (Statham) directly (sanguineously). The contractility (dp/dtmaX) was deter-mined from the pressure of the left heart ventricle (method accord-ing to Schaper et al. Arch. Kreislaufforsch. 46, 27, 1965). The heart time volume was determined by means of the cold dilution method (according to Hamilton, W.F. et al, Am. J. Physiol. 99, 543, 1932) with the aid of a fixed-program analog computer (method according to Slama, H. and Piiper, J. Kreislaufforschung 53, 322 (1964)).
For example, in the above method of testing at a dose of 1 mg/body weight of dog the average arterial mean pressure is increased by approximately 20 % and the heart time volume by approximately 100 %. The contractility (rate of pressure rise) ; is increased by approximately 70%.
Çi29 ....
This circulation-stimulating action is comparable to the action of the known drug nor-ephedrine.
The lowest blood-pressure-rising effective dose in the above animal test is, for example, 0.3 mg/kg orally and 0.1 mg/kg intravenously.
For example, 1 to 10 mg/kg, particularly 3 mg/kg orally and o.l to 1 mg/kg, particularly 0.3 mg/kg intravenously are suitable as a general dose range for the blood-pressure-rising effect (animal test as above).
Indications for which the compounds according to the invention can be considered are: disorders due to shock, hypotonia, orthostatic disorders, collapse.
The pharmaceutical preparations usually contain between 1 and 50 mg of the active component(s) according to the invention.
Theycan be dispensed, for example, in the form of tablets, capsules, pills, dragées, suppositories, aerosols or in a liquid form. For example, oily or alcoholic or aqueous solutions as well as suspensions and emulsions are suitable as liquid forms of application. Tablets containing between 1 and 50 mg or`solutions containing from 1 to 5% of active substance are preferred forms of applications.
The single dose of the active components according to the invention can be, for example, a) in the form of drugs applied orally between 5 and 40 mg b) in the form of drugs applied parenterally (for example, intravenously, intramuscularly) between 1 and 20 mg c) for drugs to be inhaled (solutions or aerosols) between 1 and 5 mg d) in the form of drugs to be applied rectally or vaginally between 5 and 30 mg.
(In all the cases the doses are relative to the free base.) For example, three times daily 1 to 3 tablets containing 5 to 40 mg of active substance can be recommended or, for example, for intravenous injection 1 to 6 times daily 1 ampule of 1 to 10 ml containing from 1 to 20 mg of substance. For oral application the minimum daily dose is, for example, 10 whereas the maximum daily dose mustnot exceed 120.
For the treatment of dogs and cats the single oral dose usually is between approximately 1 and 20 mg per kg of body weight and the parenteral dose is approximately between 0.1 and 3 mg per kg of body weight.
For the treatment of horses and cattle the single oral ~ -dose usually is between approximately 1 and 20 mg/kg of body weight and the single parenteral dose is approximately 0.1 and 3 mg per kg of body weight. ;
In mice the acute toxicity of the compounds according to the invention (expressed by the LD 50 mg/kg; method according to Miller and Tainter: Proc. Soc. Exper. Biol. a. Med. 57 (1944) 261) is, for example, for oral application above 500 mg/kg.
The drugs can be used in human medicine, in veterinary medicine and in agriculture, either alone or in mixture with other pharmacologically active substances.
Examples of Pharmaceutical Preparations Example of Tablets 25 g of (-)-nor-ephedrine salt of ~ NEMA are mixed with 25 g of colloidal silica, 5 g of cornstarch and 60 g of lac-tose. The powder is granulated with a solution of 2.5 g of methyl-oxy-propyl cellulose in approximately 80 ml of a 30% ethanol. The dried granulate is mixed with 10.5 g of cornstarch, 9 g of talc, 62.5 g of micro-crystalline cellulose and 0.5 g of magnesium stearate and then moulded into tablets in a known manner.
One tabletweighing 200 mg contains 25 mg of active substance.
.. . . ..
Example of an Injection Solution 10 mg of (-)-hydroxy-nor-ephedrine salt of (-)-NEMA
are dissolved in 200 mg of propylene glycol and the solution is made up to 2.0 ml with bidistilled water. The solution is fil-tered through a sterile filter and then filled into ampules under aseptic conditions.
~86Z9 The free acids having the general formula I also are valuable racemic-cleavage reagents for racemic bases and there-fore are important particularly for the production of optically active pharmaceutical active substances.
Example 1 (+)-~-N-(l-methyl-2-phenyl-2-hydroxy-ethyl)-maleic monoamide (abbreviated: (+)-~-NEMA) 165.4 g of maleic anhydride are dissolved in 1250 ml of warm toluene. A warm (50C) solution of 255 g of t-)-~-nor-ephedrine in 1250 ml of toluene is rapidly added dropwise while stirring, whereupon stirrin~ is continued for one hour at an internal temperature of 80C. The- solution is then cooled to room temperature. The crystallized amide acid is filtered with suc-tion and dried in vacuo at 60C.~
Yield: 419.9 g = 99.9~ of the theoretical yield.
After the recrystallization the reaction product has a melting point of 152 to 155C.
[]20 (2.S% in a 96% ethanol): +17.64.
(-)-nor-ephedrine salt - 25 g of (-)-nor-ephedrine and 41.2 g of (+)-~-NE~ are dissolved in 200 ml of acetone while hot. The salt crystallizes upon cooling.
Yield: 64.5 g = 97.6% of the theoretical yield; m.p. = 149 to 151C.
[]D (2.5% in ethanol): -64.4 Example 2 -N-~l-methyl-2-phenyl-2-hydroxy-ethyl)-maleic monoamide (abbreviated: (-)-NEMA
16.3 g of maleic anhydride are dissolved in 300 ml of toluene. A warm (50C) solution of 25.0 g of (-)-nor-ephedrine in 50 ml of toluene is added dropwise to this solution while stirring, At this temperature stirring is continued for one ;
hour, followed by cooling and filtering with suction. The pro-duct is recrystallized from acetic ethyl ester in order to purify it.
Yield: 32.6 g = 79% of the theoretical yield; m.p. = 155 to 158C.
[a]20 (5% in ethanol): -7.69 (-)-ephedrine salt 20.6 g of (-)-ephedrine and 31 g of (-)-NEMA are dis-solved in 155 ml of acetone. The solution is mixed with dry ether until the turbidity is permanent. The mixture is allowed to stand for several days at room temperature whereupon it is filtered with suction and dried in vacuo.
Yield: 37.5 g = 73% of the theoretical yield; m.p. = 118 to [a]D (1% in a 96% ethanol): -39.5 (-)-nor-ephedrine salt 25 g of t-)-nor-ephedrine and 41.2 g of (-)-NEMA are dissolved in 200 ml of acetone while hot. The solution is then cooled and the crystalline salt is iltered with suction.
Yield: 56.3 g = 85% of the theoretical yield; m.p. = 142 to 144C
la]D (1% in ethanol): +7.39.
-nor-ephedrine salt 34.5 g of (-)-~ - nor-ephedrine and 57 g of (-)-NEMA
are dissolved in 460 ml of acetic ester while hot. The solu-tion-is cooled to room temperature, filtered with suction and dried.
Yield: 90.5 g = 98.4~ of the theoretical yield; m.p. = 153 to 155C.
Ia~D (1% in ethanol): 7.70~
(-)-p-hydroxy-nor-ephedrine salt 10 g of (-)-p-hydroxy-nor-ephedrine and 14.9 g of (-)-NEMA are stirred in 125 ml of isopropanol for two hours and , then allowed to stand for 15 hours at 20C, followed by filter-ing with suction and drying at 50C in vacuo.
Yield: 23.5 g = 94.4% of the theoretical yield; m.p. = 162 to 164C. -~
[]20 (1% in ethanol): +3.8 This salt can also be obtained from racemic p-hydroxy-nor-ephedrine by utilizing the~racemate-splitting properties of the maleic amide according to example 2: - a mixture of 100 g of (+)-p-hydroxy-nor-ephedrine, 149 g of (-)-NEMA and 1.25 litres of absolute ethyl alcohol is stirred for eight hours at 20C ;
and then allowed to stand for further 16 hours. The crystallized (-)-NEMA salt of the (-)-p-hydroxy-nor-ephedrine is filtered with suction and boiled with 550 ml of isopropanol in order to purify it, whereupon it is cooled, filtered with suction and dried in vacuo at 60C.
Yield: 94.3 g = 75.7% of the theoretical yield; m.p. = 163 to [a]20 (1% in absolute ethanol): +4.1 Example 3 (-)-~-N-(l-methyl-2-phenyl-2-hydroxy-ethyl)-methyl-maleic mono-amide A mixture of 14 g of citraconic anhydride and 18.9 g of (-)-~-nor-ephedrine is stirred in 180 ml of dimethyl forma- - !
mide for five hours at 40 to 50C. The mixture is then cooled and mixed with additional 18.9 g of (-)-~-nor-ephedrine while stirring. The reaction solution obtained is filtered and the solvent is distilled off in vacuo. The remaining salt is dis-solved in cold water and after acidifyingwith hydrochloric acid it is stirred for one hour, followed by filtering with suction, washing with water and drying in vacuo at 60C.
m.p. = 137 to 140C
[a]20 (2.5% in a 96% ethanol): -1.6 ~Yi, .
1~36Z9 , Example 4 (+)-N-~l-methyl-2-phenyl-2-hydroxy-ethyl)-maleic monoamide (abbreviated: (+)-NEMA) 32.6 g of maleic anhydride are dissolved in 600 ml of toluene and, while stirring, a warm (50C) solution of 50.0 g of (+)-nor-ephedrine in 100 ml of toluene is added dropwise.
At this temperature stirring is continued for 30 minutes, followed by cooling, filtering with sucti-on, drying and crystal-lizing from acetic ethyl ester.
Yield: 63.5 g = 77.0% of the theoretical yield; m.p. = 154 to [a]D (5% in ethanol)~ + 7.8 (+)-nor-ephedrine salt 50 g of (+)-nor-ephedrine and 82.4 g of (+)-~EMA are dissolved in 400 ml of isopropanol while warm. The solution is filtered and cooled -slowly to 5C. The crystallized salt is filtered with suction and dried in'vacuo at 60C.
Yield: 118.3 g = 89.5 g of the theoretical yield; m.p. = 141 to 143C.
20 I~] DO ( 1% in ethanol): -7.40 (+)-~-nor-ephedrine salt 34.5 g of ~+)-~-nor-ephedrine and 57 g of (+)-NEMA
are dissolved in 460 ml of acetic ester while hot. After cool-ing to room temperature the solution is filtered with suction and dried.
Yield; 90.S g = 98.4% of the theoretical yield; m.p. = 153 to 156C.
1~]D (1% in ethanol): -7.70 Example 5 (-)-N-(l-metbyl-2-p-hydroxy-phenyl-2-hydroxy-ethyl~-maleic monoamide (abbreviated: (-)-p-hydroxy-NEMA) S0 g of (-)-p-hydroxy-nor-ephedrine along with 29.3 g _ 20 -.
. . ,.: .. :
2g of maleic anhydride are stirred in 100 ml of dimethyl formamide.
After a weakly exothermic reaction fades the mixture is heated to 80C and kept for 1 hour at this temperature and is then mixed with 100 ml of water and stirréd for one hour. It is filtered with suction the next day and dried in vacuo.
Yield: 76.1 g = 96% of the theoretical yield; m.p. = 146 to 148C.
It is subsequently purified with cold isopropanol, filtered with suction and dried.
m.p. = 150 to 152C
[~]D (2% in a 96% ethanol): -13.05 Example 6 (+)-N-(l-methyl-2-p-hydroxy-phenyl-2-hydroxy-ethyl)-maleic monoamide (abbreviated: (+)-p-hydroxy-NEMA) 100 g of (+)-p-hydroxy-nor-ephedrine and 60.8 g of maleic anhydride are stirred in 150 ml dimethyl formamide.
After a weakly exothermic reaction fades the mixture is heated ~ -to ~0C and kept for one hour at this temperature and is then mixed with 100 ml of water and stirred for one hour. It is filtered with suction the next day and dried in vacuo.
yield~ 120 g of pure (+)-p-hydroxy-NE~A; m.p. = 151 to 153C
ta]20 (2% in a 96% ethanol): +12.9 Isopropanol can also be used as the solvent instead of dimethyl formamide~
_ 21 -
Claims (10)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing hemiamides of unsaturated aliphatic dicarboxylic acids having the general formula (I) wherein R1,R2 and R3 are identical or different and represent hydrogen, a halogen atom, a hydroxy group, a methyl group or a methoxy group or two of these radicals together represent a methylene-dioxy group, R4 represents hydrogen or methyl group, the radicals R6 and R7 represent, independently of each other, hydrogen or C1-C4-alkyl groups and n is 0 or 1, the N-[2-(3-hydroxy-phenyl)-2-hydroxy-ethyl]-maleic monoamide being excluded in the case of the free acids, or pharmaceutically acceptable salts thereof which comprises reacting a compound having the formula (II) with a compound of the formula X - CO - CR6 = CR7 - CO2H (III) in which compounds the radicals R1-R4,R6 and R7 have the meanings defined hereinbefore and wherein oxy groups present and the car-boxy group of the compound III may also be protected and X repre-sents a halogen atom, a hydroxy group, a C1-C6-alkoxy group, a cyano-methoxy radical, a carboxy-methoxy radical or an aryl-oxy group or X forms with the free carboxy group a five-membered acid anhydride ring and when required, the compounds obtained are converted into said salts by reaction with amines or basic metal derivatives.
2. Hemiamides of unsaturated aliphatic dicarboxylic acids having the general formula (I) wherein R1, R2 and R3 are identical or different and represent hydrogen, a halogen atom, a hydroxy group, a methyl group or a methoxy group or two of these radicals together represent a methylene dioxy group, R4 is hydrogen or a methyl group, the radi-cals R6 and R7 represent, independently of each other, hydrogen or C1-C4-alkyl groups and n is 0 or 1, the N-[2-(3-hydroxy-phenyl)-2-hydroxy-ethyl]-maleic monoamide being excluded in the case of the free acids or pharmaceutically acceptable salts thereof when-ever prepared or produced by the process of Claim 1, or an obvious chemical equivalent thereof.
3. A process as claimed in Claim 1, in which the reactants R3, R6 and R7 represent hydrogen, R4 represents a methyl group and R1 is hydrogen and R2 represents a hydroxy group or the two radicals R1 and R2 represent a hydroxy group.
4. A hemiamide of formula I given in Claim 1, or a pharmaceutically acceptable salt thereof wherein R1, R2, R3, R4, R6 and R7 are as in Claim 3 and n is as in Claim 1 whenever pre-pared or produced by the process of Claim 3 or an obvious chemical equivalent thereof.
5. A process as claimed in Claim 3, in which the products obtained are reacted with racemic or optically active .beta.-phenyl-ethyl amine, which - in the .beta. position - can also contain a hydroxy group, in the .alpha. position it can contain a methyl group and in the phenyl ring one or two hydroxy groups.
6. A salt of a hemiamide of formula I given in Claim 1, wherein R1, R2, R3, R4, R6 and R7 are as in Claim 3 and n is as in Claim 1 with racemic or optically active .beta.-phenyl-ethyl-amine, which - in the .beta. position - can also contain a hydroxy group, in the .alpha. position it can contain a methyl group and in the phenyl ring one or two hydroxy groups, whenever prepared or produced by the process of Claim 5, or an obvious chemical equi-valent thereof.
7. A process as claimed in Claim 5, wherein the hydroxy groups in the phenyl ring of the .beta.-phenyl-ethyl amine are in at least one of the 4 position, the 2 position and the 3,5 position.
8. A salt of a hemiamide of formula I given in Claim 1, wherein R1, R2, R3, R4, R6 and R7 are as in Claim 3 and n is as in Claim 1, with racemic or optically active .beta.-phenyl-ethyl amine, which - in the .beta. position - can also contain a hydroxy group, in the .alpha. position it can contain a methyl group and in the phenyl ring one or two hydroxy groups, wherein the hydroxy groups in the phenyl ring of the .beta.-phenyl-ethyl amine are in at least one of the 4 position, the 2 position and the 3,5 position, whenever prepared or produced by the process of Claim 7, or an obvious chemical equivalent thereof.
9. A process according to Claim 3, in which the product obtained is reacted with racemic or optically active .beta.-phenyl-ethyl amine, which - in the .beta. position - can also contain a hydroxy group, in the .alpha. position it can contain a methyl group and in the phenyl ring one or two hydroxy groups.
10. A salt of a hemiamide of formula I given in Claim 1, wherein R1, R2, R3, R4, R6 and R7 are as in Claim 3 and n is as in Claim 1, with racemic or optically active phenyl ethyl amine which in the .beta. position - can also contain a hydroxy group, in the .alpha. position it can contain a methyl group and in the phenyl ring one or two hydroxy groups, whenever prepared or produced by the process of Claim 9, or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB52422/77 | 1977-12-16 | ||
| GB5242277 | 1977-12-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1108629A true CA1108629A (en) | 1981-09-08 |
Family
ID=10463869
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA318,131A Expired CA1108629A (en) | 1977-12-16 | 1978-12-18 | Maleic acid halfamides |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US4191777A (en) |
| JP (1) | JPS5490131A (en) |
| CA (1) | CA1108629A (en) |
| DD (1) | DD139843A5 (en) |
| DE (1) | DE2854070A1 (en) |
| ES (1) | ES476031A1 (en) |
| FR (1) | FR2411830A1 (en) |
| IT (1) | IT7852316A0 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1735266B1 (en) | 2004-04-15 | 2009-06-24 | Emmellen Biotech Pharmaceuticals Limited | Process for preparation of optically active 1-erythro-2-amino-1-phenyl-1-propanol |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3222395A (en) * | 1965-12-07 | Maleamic ackd derivatives | ||
| US2275809A (en) * | 1939-02-09 | 1942-03-10 | Richard G Roberts | Reaction of epinephrine with amino acids and products thereof |
| FR1537803A (en) * | 1966-07-14 | 1968-08-30 | Diwag Chemische Fabriken Gmbh | Process for making acylaminophenolalkanols |
| CH499495A (en) * | 1968-03-15 | 1970-11-30 | Bracco Ind Chimica Spa | Process for the preparation of new dicarboxylic acid mono-N- (a-phenylethyl) amides and use of the same for the separation of racemic bases |
| JPS5069039A (en) * | 1973-10-23 | 1975-06-09 |
-
1978
- 1978-12-05 FR FR7834177A patent/FR2411830A1/en not_active Withdrawn
- 1978-12-13 US US05/969,068 patent/US4191777A/en not_active Expired - Lifetime
- 1978-12-14 DE DE19782854070 patent/DE2854070A1/en not_active Withdrawn
- 1978-12-14 JP JP15376178A patent/JPS5490131A/en active Pending
- 1978-12-14 DD DD78209762A patent/DD139843A5/en unknown
- 1978-12-15 ES ES476031A patent/ES476031A1/en not_active Expired
- 1978-12-15 IT IT7852316A patent/IT7852316A0/en unknown
- 1978-12-18 CA CA318,131A patent/CA1108629A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR2411830A1 (en) | 1979-07-13 |
| DD139843A5 (en) | 1980-01-23 |
| US4191777A (en) | 1980-03-04 |
| ES476031A1 (en) | 1979-06-16 |
| DE2854070A1 (en) | 1979-06-28 |
| IT7852316A0 (en) | 1978-12-15 |
| JPS5490131A (en) | 1979-07-17 |
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